Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations.

Jonathan Rock,Gildardo Rivera,Omar Espino,Debasish Bandyopadhyay,Navin B Patel,Shaila A Shetu,Daniel Garcia,Rosa Moo-Puc,Manuel J Chan-Bacab

doi:10.3389/fchem.2021.725892

Abstract

World Health Organization (WHO) identified twenty tropical disease categories as neglected tropical diseases (NTDs)1. Chagas’ disease (also known as American trypanosomiasis) and leishmaniasis are two major classes of NTDs. The total number of mortality, morbidity, and disability attributed each year due to these two categories of diseases in magnitudes is much higher than the so-called elite diseases like cancer, diabetes, AIDS, cardiovascular and neurodegenerative diseases. Impoverished communities around the world are the major victim of NTDs. The development of new and novel drugs in the battle against Chagas’ disease and leishmaniasis is highly anticipated. An easy and straightforward on-water green access to synthesize benzopyrazines is reported. This ultrasound-assisted procedure does not require any catalyst/support/additive/hazardous solvents and maintains a high atom economy. A series of eleven benzopyrazines has been synthesized, and most of the synthesized compounds possess the drug-likeness following Lipinski’s “Rule of 5”. Benzopyrazines 3 and 4 demonstrated moderate leishmanicidal activity against L. mexicana (M378) strain. The selective lead compound 1 showed good leishmanicidal, and trypanocidal activities (in vitro) against both L. mexicana (M378) and T. cruzi (NINOA) strains compared to the standard controls. The in vitro trypanocidal and leishmanicidal activities of the lead compound 1 have been validated by molecular docking studies against four biomolecular drug targets viz. T. cruzi histidyl-tRNA synthetase, T. cruzi trans-sialidase, leishmanial rRNA A-site, and leishmania major N-myristoyl transferase.

Highlights

Heterocycles play a significant role in drug discovery research
We report an ultrasoundassisted on-water green synthesis of diversely substituted benzopyrazine derivatives (Scheme 1) and subsequent in vitro trypanocidal and leishmanicidal evaluation of these compounds
The dicarbonyls’ electrophilicity was varied by introducing p-nitro, p-fluoro (EWG) or methyl (EDG) in the dicarbonyl system

Summary

Introduction

Heterocycles play a significant role in drug discovery research. A considerable number of the small molecule inhibitors are heterocyclic compounds. A few naturally occurring antibiotics and nutrients like vitamin B2 contain benzopyrazine moiety as a core in their structures (Figure 1). This scaffold is present as the key structural motif in many biologically active compounds, which includes anticancer (Lee et al, 2012; Bandyopadhyay et al, 2013; Qi et al, 2018), antibacterial (ElAttar et al, 2018), antitubercular (Achutha et al, 2013), antiebola (Loughran et al, 2016), antifungal (Carta et al, 2001) among many others. A few synthetic procedures, reported in the immediate past, include the synthesis of benzopyrazines under the catalytic influence of Co3O4 nanocages based nickel catalyst (Sharma et al, 2021), iron-catalyzed transfer hydrogenative condensation (Putta et al, 2021), sodium hydroxide-mediated hydrogen-transfer (Wang et al, 2021), as well as the uses of tungstophosphoric acid-support (Kumaresan et al, 2020), and Co-based nanocatalyst (Panja et al, 2020)

Methods

Results

Discussion

Conclusion